Socioeconomic impacts of clinical foot-and-mouth disease and a risk-based partial vaccination campaign for smallholders in Lao People's Democratic Republic.

Foot-and-mouth disease (FMD) is endemic in Lao People's Democratic Republic (PDR). A risk-based partial vaccination campaign was implemented in Champasak, Savannakhet and Xiengkhouang Provinces in Lao PDR in 2016-2020, which had limited effects on reducing the circulation of FMD virus. The objectives of this study were to measure the socioeconomic effects of (i) a clinical FMD occurrence and (ii) the vaccination campaign on livestock production performance of smallholders in Lao PDR in 2016-2020. Two questionnaire surveys were conducted at the beginning (2016) and the end (2020) of the campaign, involving 1609 smallholders in 160 villages comparing areas with and without FMD control. Mixed-effect multivariable regression models were fitted to measure the association between livestock production parameters at the household level (rates of birth, sale, purchase, and death, sale price, costs, gross gains and net gains) and (i) a clinical FMD occurrence and (ii) the vaccination campaign, while adjusting for village, herd size, province, vaccination status and FMD knowledge. We found no significant difference in annual household-level costs, gains and net gains by due absence of FMD. However, smallholders with FMD had a 52% higher cattle death rate, a 43% lower goat sale rate and a 78% lower pig sale price than those without FMD. Smallholders with FMD also had a lower purchase rate of livestock (cattle -15% and pigs -93%) compared with those without FMD. There was a general improvement in livestock production in target villages over the 5 years of the vaccination campaign, whereas there was an overall decline in non-target villages, resulting in USD 218 higher net gains in target villages in 2020 compared with non-target villages, possibly due to reduced severity of disease and improved awareness on FMD and general livestock health. The findings of this study will help improve strategies for sustainable and efficient FMD control in Lao PDR, while the challenges and importance of gaining participation by smallholders are highlighted.

Impact of risk-based partial vaccination on clinical incidence and seroprevalence of foot and mouth disease in Lao PDR.

Foot and mouth disease (FMD) is endemic in the Lao People's Democratic Republic (PDR) and it causes economic loss to smallholder husbandry systems. An intervention programme based on a risk-based partial vaccination strategy was implemented in three provinces of Lao PDR (Champasak, Savannakhet and Xiangkhouang) to immunise domestic cattle and buffalo during 2016-2020. Two cross-sectional surveys were conducted in 2016/17 and 2020 to evaluate the impact of the vaccination programme on the prevalence of FMD virus exposure and clinical incidence of the disease. A total of 212 villages were visited during the two surveys, collecting 1609 household-level questionnaire results and 5931 blood samples of domestic cattle and buffalo. Blood samples were tested for the presence of antibodies to the non-structural proteins of FMD virus, and seroprevalence of 42.5 and 47.5% in 2016/17 and 2020, respectively were found. Multivariable regression analysis indicated that the efficacy of the FMD vaccination programme for reducing FMD virus circulation varied by province. In general, the incidence of clinical FMD increased toward the end of the 5-year intervention period, coinciding with a reduction of vaccine coverage in the last 2 years of the period. The findings suggest that the risk-based vaccination strategy achieved a marginally protective effect against the circulation of FMD virus with the possible limiting factors being operational constraints of public veterinary services, lack of farmers' compliance and unsustainable funding. We conclude that consistent resource availability and higher vaccination coverage is required to successfully control FMD with a risk-based vaccination strategy in Lao PDR.

Development of simulation models for transmission of Salmonid Rickettsial Septicaemia between salt water fish farms in Chile.

This study aimed at estimating parameters representing between-farm transmission of Salmonid Rickettsial Septicaemia (SRS) in Chile, and developing and validating simulation models to predict weekly spread of SRS between farms in Los Lagos (Region 10), using InterSpread Plus. The model parameters were estimated by analyses of the historical SRS outbreak data. The models incorporated time and distance-dependent transmission kernels, representing the probabilities of waterborne spread of SRS between farms. Seven candidate transmission kernels were estimated, with varying maximum distance of between-farm SRS spread (15-60 km). Farms were categorized by size (small; medium; large) and species (Coho salmon; Atlantic salmon; rainbow trout). The time that it took a farm to recover from infection was parameterized to be shortest for small Coho farms (median: 7 weeks), followed by medium and large Coho farms (median: 25 weeks), Atlantic salmon farms (median: 42 weeks, any size) and rainbow trout farms (median: 43 weeks, any size). The relative infectiousness parameters of rainbow trout farms were 1.5-6.3 times that of Coho or Atlantic salmon, or those of large farms was 1.3-4.2 times that of small or medium farms. The models predicted SRS prevalence in Region 10 between 2013 and 2015 (79 weeks) with 76.5%-93.0% overall accuracy. The model with a transmission kernel of <20 km (P20) achieved a maximum overall accuracy (93.0%). Within each neighbourhood, the accuracy of P20 varied between 32.4% and 88.1%; 13/20 neighbourhoods had a reasonable temporal agreement between the simulated and actual dynamics of SRS (within 5th-95th percentiles), but 5/20 neighbourhoods underestimated and 2/20 overestimated the SRS spread. The model could be used for evaluation of semi-global control policies in Region 10, while addition of other factors such as seasonality, ocean currents, and movement of infected fish may improve the model performance at a finer scale.

Real-Time Standard Analysis of Disease Investigation (SADI)-A Toolbox Approach to Inform Disease Outbreak Response.

An incursion of an important exotic transboundary animal disease requires a prompt and intensive response. The routine analysis of up-to-date data, as near to real time as possible, is essential for the objective assessment of the patterns of disease spread or effectiveness of control measures and the formulation of alternative control strategies. In this paper, we describe the Standard Analysis of Disease Investigation (SADI), a toolbox for informing disease outbreak response, which was developed as part of New Zealand's biosecurity preparedness. SADI was generically designed on a web-based software platform, Integrated Real-time Information System (IRIS). We demonstrated the use of SADI for a hypothetical foot-and-mouth disease (FMD) outbreak scenario in New Zealand. The data standards were set within SADI, accommodating a single relational database that integrated the national livestock population data, outbreak data, and tracing data. We collected a well-researched, standardised set of 16 epidemiologically relevant analyses for informing the FMD outbreak response, including farm response timelines, interactive outbreak/network maps, stratified epidemic curves, estimated dissemination rates, estimated reproduction numbers, and areal attack rates. The analyses were programmed within SADI to automate the process to generate the reports at a regular interval (daily) using the most up-to-date data. Having SADI prepared in advance and the process streamlined for data collection, analysis and reporting would free a wider group of epidemiologists during an actual disease outbreak from solving data inconsistency among response teams, daily "number crunching," or providing largely retrospective analyses. Instead, the focus could be directed into enhancing data collection strategies, improving data quality, understanding the limitations of the data available, interpreting the set of analyses, and communicating their meaning with response teams, decision makers and public in the context of the epidemic.

Computerized surveillance system of tuberculosis in Japan: its evolution, achievement and challenges.

The nationwide computerized tuberculosis (TB) surveillance system was revised in 2007. It was developed to be user-friendly and to allow the evaluation of current TB problems and control issues in Japan. All public health centers in Japan (518 as of April 2007) have system terminals connected to a central computer, and the data entered at these terminals are sent to the online central computer excluding personal identification data. All the figures and tables in this paper were created using the annual report database which are compiled from this system. The revision in 2007 added many new functions to the system, such as a function for automatically sending data upon transfer. The monitoring information for assisting case management of TB patients by the DOTS was also enhanced. The algorithm for classifying treatment outcomes automatically based on data entered regarding cancellations from registration, bacteriological results and drug usage each month was revised. The proportion of "Failed" and "Defaulted" combined was 4.6% among new sputum smear positive pulmonary TB patients newly registered in 2009, while "Died" accounted for as high as 19.3%, due largely to a high percentage of the elderly. A new system for contact examination management is provided as a subsystem. Feedback of data analyses has been strengthened by various methods. This TB surveillance system is indispensable for implementing the evidence-based TB control program in Japan. An important role of the Research Institute of Tuberculosis is to support the planning and execution of TB control with provision of useful epidemiological information from the system.

[Management of adverse effects with antituberculosis chemotherapy].

Tuberculosis has now become a curable disease with chemotherapy. So it is natural that the present issues in tuberculosis management are focused on how to complete standard chemotherapy. In this context, management of adverse effects constitutes an essential part of antituberculosis chemotherapy, as well as directly observed therapy. In this symposium, discussions were held about three major subjects on this issue. First, hepatotoxicity develops frequently and has sometimes fatal outcome, which makes it the most problematic adverse effect. "Management of hepatotoxicity during antituberculosis chemotherapy" was published by the Japanese Society for Tuberculosis (JST) in 2006. Dr. Shinsho Yoshiba evaluated this recommendation and pointed out that the criteria for discontinuation of drug based on AST, ALT and bilirubin levels is too sensitive and the concept of predicting fulminant hepatic failure (FHF) is lacking. He stressed the importance of monitoring serum prothrombin time for predicting FHF. Next, allergic drug reaction such as fever or skin rash often causes distress, although rarely fatal. As isoniazid (INH) and rifampicin (RFP) are key drugs for the cure, readministration of these drugs is often attempted by desensitization therapy. "Recommendation about desensitization therapy of antituberculosis drugs" was also published by JST in 1997. Dr. Yoshihiro Kobashi reported high success rates of 79 percent for INH and 75 percent for RFP according to this recommendation. He also reported correlated factor with the success, such as the longer period from the discontinuation to the desensitization therapy and lower doses of drugs at starting desensitization. Finally, we sometimes experience transient worsening of radiographical findings and general symptoms during antituberculosis chemotherapy. This is presumed to be due to allergic reaction to dead bacilli without requiring discontinuation of the drug. Differential diagnosis includes drug-induced pneumonia requring discontinuation and true worsening of pulmonary tuberculosis due to drug resistance requiring change in therapy. Dr. Masanori Akira reported that presence of ground-glass attenuation and/or consolidation by HRCT suggests transient worsening or drug-induced pneumonia, whereas presence of centrilobular nodules and/or tree-in bud suggests true worsening. We believe that these findings from the symposium will add useful information for management of adverse effects and be helpful for implementation of antituberculosis chemotherapy. (1) Hepatotoxicity of antituberculosis drugs: Shinsho YOSHIBA (Sempo Tokyo Takanawa Hospital) Antituberculosis drugs are sometimes hepatotoxic. Doctors who are responsible for the treatment of patients with tuberculosis should always be aware of their hepatotoxicity, because it seldom leads to fulminant hepatic failure. The Japanese Society for Tuberculosis proposed criteria based on the levels of AST, ALT and bilirubin for the prevention of such grave hepatic injury in 2006. In recent years attempts have been made to predict fulminant hepatic failure (FHF) before patients develop coma. Yoshiba's formula using prothrombin time, etiology, cholinesterase and bilirubin is widely accepted as useful to predict FHF. Introduction of the formula to this area is recommended. (2) Desensitization therapy for allergic reactions of antituberculous drugs: Yoshihiro KOBASHI, Mikio OKA (Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School) We evaluated the usefulness of desensitization therapy for patients showing allergic reactions of INH and RFP according to the guideline proposed by the Japanese Society for Tuberculosis. Adverse reactions were 22 patients with drug eruption, 22 with drug fever and 6 with drug fever plus eruption. The clinical effect of desensitization therapy was good in 27 out of 36 patients for RFP (75%), and in 19 out of 24 patients for INH (79%). The comparative study between patient group with success desensitization therapy and that with failure desensitization therapy was not a significant difference except for initiation period of desensitization therapy. (3) The imaging features of early transient radiographic progression, true worsening of TB, and drug induced pneumonitis during TB treatment: Masanori AKIRA (Department of Radiology, NHO Kinki-chuo Chest Medical Center) HRCT findings of the new lesions in the early transient radiographic progression are enlargement or confluence of the original lesions, development of areas of ground-glass attenuation and/or consolidation ipsilateral to the original lesion, and development of areas of ground-glass attenuation and/or consolidation in the subpleural region contralateral to the lesion. These CT findings may suggest a local hypersensitivity reaction to drug or massive dead tubercle bacilli per se. In contrast, CT findings of patients with multiple drug-resistant tuberculosis and true progression are centrilobular nodules, tree-in-bud appearance, nodules, and cavitation. These CT findings may suggest a bronchogenic spread from the original tuberculous lesions.

Contact investigation in a primary school using a whole blood interferon-gamma assay.

OBJECTIVES: To evaluate the usefulness of QuantiFERON-TB Gold (QFT-G) for children. METHODS: Students in a primary school exposed to a tuberculosis patient were investigated using the tuberculin skin test (TST), chest X-ray examination and sequential QFT-G tests. RESULTS: The first QFT-G test was conducted one month after the end of exposure for 308 of the 313 children, with 6 (1.9%) positive. TST results were obtained from 306 of the students at 2 months after exposure, and 200 (65.4%) had induration > or =5mm. A second QFT-G test, a further month later, and a third QFT-G test, six months after exposure, found an additional 2 positive and one weakly positive, respectively. Overall, the rate of QFT-G positivity was 9.8% (4/41) for close contact children (> or =90h exposure), significantly higher than for casual contacts (< or =18h exposure; 1.8%, 5/272; p=0.020), whereas there was no significant difference in TST positive rates (p=0.078). CONCLUSIONS: These data suggest that QFT-G has the same performance characteristics in BCG vaccinated children as it does in adults. The observation that none of the 297 students who were QFT-G negative had developed active TB after 3 years of follow-up suggests that QFT-G has a very high negative predictive value.

[Tuberculosis control in Shinjuku Ward, Tokyo--promoting the DOTS program and its outcome].

OBJECTIVES: The objectives were to report how to promote tuberculosis (TB) control including DOTS (Directly Observed Treatment, Short-course) programs, and to evaluate the results of TB control programs in Shinjuku Ward (Shinjuku-ku). SETTING AND CHARACTERISTICS: Inhabitants and TB patients in Shinjuku Ward. Shinjuku Ward is located in the center of metropolitan Tokyo and has typical urban TB problems, such as high incidence rate and TB among foreigners and the homeless. The TB incidence rates in Shinjuku Ward decreased from 83.9 per 100,000 population in 1999 to 42.5 per 100,000 population in 2006, however, the rates were still two times higher than the national average. Therefore, one of the important TB programs in Shinjuku has been to actively detect cases among high-risk groups such as foreigners and the homeless. METHODS: We observed the trend of case detection rates by health examination with chest X-ray among different high-risk groups, and compared the treatment outcomes before and after DOTS program execution. We also reviewed the changes of re-treatment rates and drug resistance rates. RESULTS: The case detection rates of TB by health examinations of foreign students at Japanese language schools decreased from 0.49% in 1996 to 0.13% in 2006 (p = 0.021). Although the case detection rates decreased, they were still about 26 times higher than those of Japanese students. While, the case detection rates among the homeless remained high with 4.7%, 3.3%, 4.5% and 3.6% in 1999-2002, respectively, since 2003, however, they had decreased and no TB cases were detected in 2005-2006. The DOTS program for homeless TB patients has been carried out since 2000 and that for the foreigners since 2003. The rates of defaulting during treatment before DOTS were very high among both homeless patients (21.4%) and foreigners (29.8%) in 1998-1999. However, after the introduction of DOTS program, those rates declined to 10.4% (p = 0.014) among the homeless and 7.8% (p = 0.002) among foreigners in 2002-2004. The proportion of newly notified patients with previous TB treatment and those with multi-drug resistant TB (MDR-TB) have also decreased after the introduction of DOTS programs. From 2000-2002 to 2003-2006, the re-treatment rates decreased from 19.4% to 10.0% (p < 0.001) and MDR-TB rates decreased from 1.6% to 0.2% (p = 0.042), respectively. DISCUSSION: The key points of TB control in Shinjuku Ward are to detect TB cases early especially among the high-risk groups, and to assist all TB patients to complete their treatment. In order to expand this strategy, besides promoting active case findings among high-risk groups, we have developed many types of DOTS programs, considering each patient's lifestyle and cooperating with school teachers at schools, pharmacists at pharmacies, home-care specialists at homes or facilities for the elderly, and so on. Among others, a major premise for the homeless and some other socially disadvantaged patients was to guarantee the provision of medicine and living by introducing social welfare services, before starting DOTS programs. This approach might have helped to reduce the defaulting rate, relapse rate and MDR-TB rate.

[Relapse rate of pulmonary tuberculosis within two years following completion of twice weekly intermittent chemotherapy].

OBJECTIVE: To evaluate the relapse rate after treatment of a twice weekly intermittent chemotherapy during continuation phase in the patients with pulmonary tuberculosis in two years period after completion of chemotherapy. METHODS: The patients with drug susceptible pulmonary tuberculosis treated with 2HRZE/4H2R2 under the supervision by the pharmacists or the patients treated with 2HRZE/4HR by self-administration were followed-up for two years after completion of chemotherapy. RESULTS: A total number of 135 pulmonary tuberculosis patients were treated with 2HRZE/4H2R2, 3 of 135 discontinued this intermittent treatment, and 11 of 135 completed chemotherapy was excluded from the relapse analysis, 105 out of the remaining 121 were followed-up for more than 6 months. On the other hand 240 patients were treated with 2HRZE/4HR, 37 out of 240 were excluded from the analysis, 147 of the remaining 203 were followed-up for more than 6 months. The relapse rate of this intermittent chemotherapy 1.89/100 person-year was similar to the relapse rate 1.86/100 person-year among 147 treated with daily regimen by self-administration. This difference was not statistically significant (z = 0.36, P = 0.14). CONCLUSION: As regards relapse rate, this 2HRZE/4H2R2 regimen is effective and useful for the expansion of DOT, and it should be expanded nationally in Japan.

[Implementation and evaluation by a population-based RFLP analysis in an urban area, Shinjuku city, Tokyo--the possibility of application for contact investigations].

OBJECTIVES: The objectives were to examine Mycobacterium tuberculosis transmission patterns by RFLP analysis in Shinjuku city, and to elucidate more effective methods of contact investigations. METHODS: We applied RFLP analysis to 389 M. tuberculosis isolates from 402 TB patients registered in Shinjuku city from September 2002 though August 2006. RESULTS: Forty-six clusters consisting of 155 TB patients (average 3.4 people per cluster) were identified (proportion of clustering: 39.8%). The clustering rates were 34.5% among general patients, and 57.8% among homeless patients, and the latter was higher than that of non-homeless patients (odds ratio: 2.6, 95% CI; 1.6-4.1, p < 0.001). On the other hand, the clustering rates were only 19.4% among foreigners (odds ratio: 0.5, 95% CI; 0.2-1.2, p = 0.090). Twenty-eight of 46 clusters (60.9%) were consisted of mixture of general patients, homeless patients and foreigner patients. Thus, RFLP analysis can detect the transmission route which can not be identified by the routine contact examination, thus enabling contact investigations extended to the appropriate persons. DISCUSSION: The homeless clustering rate was significantly high. This suggests that the proportion of transmission among the homeless patients might be high. However, many clusters were composed of a mixture of homeless patients and non-homeless patients, so transmission patterns are not easy to identify. It is not always true that transmission of tuberculosis to non-homeless patients took place from homeless patients. Clustering rates among homeless patients are high, therefore taking countermeasures for the homeless patients is an effective way to prevent the spread of tuberculosis. Introduction of RFLP analysis is a practical epidemiological methodology to investigate the source of infection and transmission route of infection, and can be applied to contact investigations. If RFLP analysis can be applied in a larger area, yearly changes of notification rates and molecular epidemiological clustering rates will provide indices for preventive measures against tuberculosis.

Biological and molecular characteristics of Mycobacterium tuberculosis clinical isolates with low-level resistance to isoniazid in Japan.

We reevaluated the BACTEC MGIT 960 antimicrobial susceptibility testing system (MGIT 960 AST) by using 1,112 isolates of Mycobacterium tuberculosis. When the results of MGIT 960 AST were compared with that of the proportion method using Ogawa medium (Ogawa PM), discrepant results were obtained for 30 strains with isoniazid, all resistant by MGIT 960 AST but susceptible by Ogawa PM. For 93% of the strains that produced discrepant results, the MIC was 0.4 or 0.8 microg/ml, showing resistance by the proportion method using Middlebrook agar plates. Furthermore, it was also established by analyses of the katG and inhA genes that strains resistant only by MGIT 960 AST have a low level of isoniazid (INH) resistance, indicating that MGIT 960 AST is a reliable method. Ninety-six strains were resistant to 0.1 microg/ml INH by MGIT 960 AST. When they were divided into three groups, Low-S (susceptible at 0.2 microg/ml), Low-R (resistant at 0.2 microg/ml), and High-R (resistant at 1.0 microg/ml), by Ogawa PM, 43.3% of the Low-S strains had mutations in the promoter region of inhA and no mutations were detected in katG codon 315, while 61.7% of the High-R strains had katG codon 315 mutations or a gross deletion of katG. These results suggest that mutations in inhA are associated with low-level resistance to INH and katG codon 315 mutations are associated with high-level resistance to INH. In addition, the analyses demonstrated some relationship of mutations in the inhA gene with ethionamide resistance for the Low-S strains, but not for the High-R strains.

[Case of multi-drug resistant pulmonary tuberculosis with bilateral cavitary lesions successfully treated by surgical treatment].

A case was 38 years old male. He was pointed out abnormal shadow on chest X-ray and complained respiratory infection symptoms. He had not past history of tuberculosis. He was diagnosed as multi-drug resistant tuberculosis (MDR-TB) in a certain hospital and was referred to our hospital to undergo treatment. His drug sensitivity test by Ogawa medium was resistant to all anti-tuberculosis drugs except for kanamycin (KM) and enviomycin (EVM). His chest X-ray revealed large cavities in the right upper field and infiltrations in the right lower field and small cavitary lesions in the left lower field. The right pneumonectomy was done because he took anti-tuberculosis drugs but his sputum examinations continued to be smear and culture positive without improvement of the lesions. After the surgical treatment (right pneumonectomy), he continued anti-tuberculosis drugs therapy and the chest X-ray improved including the collapse of left lower cavitary lesions. This case was a difficult case to treat because of bilateral cavitary lesions. However he was successfully treated by the surgical treatment.

[Anti-tuberculosis chemotherapy].

The era of the modem chemotherapy in the treatment of tuberculosis has started by the discovery of streptomycin in 1943. Soon after the introduction of SM, it became evident that drug-resistance against streptomycin (SM) quickly emerged when used singly, and the combination therapy with para-aminosalicylate (PAS) and isoniazid (INH), both of which were developed a little later, had been the standard regimens for the treatment of tuberculosis. But, long-term therapy, more than a year, sometimes of two or three years, was required to get recovered from tuberculosis by three-drug combination therapy of SM-PAS-INH. Introduction of rifampicin (RFP) in 1966 and re-evaluation of pyrazinamide (PZA) in early 1970's have brought a revolutionary change in the concept of tuberculosis chemotherapy, and very potent six-month regimen, consisting of two-month initial intensive phase (INH-RFP-PZA and EB or SM) and four-month maintenance phase (INH-RFP) has been established as the global standard regimen. Tuberculosis chemotherapy has liberated tuberculosis patients from lengthy stay in sanatoria or hospitals. Now, tuberculosis patients could be and should be treated by the intensive short-course chemotherapy under ambulatory settings. One of the most serious obstacles of ambulatory treatment is the incompliance of the patients to the prescribed regimen. Obvious outcome of such incompliance is the treatment failure at the level of individual patients and also the prevalence of multidrug-resistant- (MDR-) and extensively drug-resistant- (XDR-) tuberculosis all over the world. MDR-and XDR-tuberculosis are already threatening tuberculosis control policy in some countries and districts in the world. Early diagnosis of infectious patients and successful treatment of newly diagnosed patients under DOTS are the most recommendable strategies to prevent the emergency of MDR-and XDR-tuberculosis worldwide. In Japan, the policy of tuberculosis treatment has been more or less diverged from the global standards, namely, higher rate of hospitalization, longer hospitalization periods, and longer treatment. One of the most important reasons for such cost-effectively inefficient practices is the lack of reliable and practical DOT system for ambulatory treatment. Recently, we successfully completed a trial to implement a DOT system in which the city-pharmacists served as the observer. We believe that this system is well acceptable for both city-pharmacies and tuberculosis patients, and expect to be adapted through the whole country. New anti-tuberculosis drugs which enable the intermittent therapy of much shorter duration are eagerly expected.

[Comparative study of bactec MGIT 960 AST and conventional proportion method using Ogawa medium for the drug susceptibility testing of Mycobacterium tuberculosis to isoniazid].

OBJECTIVE: To evaluate the accuracy of drug susceptibility testing to isoniazid with BACTEC MGIT 960 (MGIT AST) comparing with the standard proportion method using Ogawa medium. METHOD: A total of 1109 M. tuberculosis strains, which were selected from the collection of RYOKEN drug resistance survey in 2002, were selected and subjected to the susceptibility testing to isoniazid using MGIT AST and 1% Ogawa standard methods. The results from MGIT AST were compared with the judicial diagnosis by Ogawa. The sensitivity to detect drug resistance, the specificity for susceptible strain, the efficiency of overall agreement, and kappa coefficient were calculated to evaluate the performance. The treatment process, outcome and prognosis were analysed for the patients on whom the tests showed discrepant results. RESULTS: Compared with the judicial results, the sensitivity, specificity, efficiency, and kappa coefficient of MGIT AST were 100%, 97.1%, 97.3%, and 0.798, respectively. The strains, which showed discrepant results between MGIT AST and Ogawa, were all susceptible by Ogawa and resistant by MGIT AST. A total of 11 out of 30 discrepant cases were followed clinically and no relapse cases were identified, irrespective of the modification of the treatment regimen. As for the proportion of primary INH drug resistance in the present study, it was 5.3% with MGIT AST but was 2.7% with Ogawa, and the difference was statistically significant (p = 0.005). DISCUSSION: The discrepancies on the results of drug susceptibility testing of M. tuberculosis strains to isoniazid between MGIT AST and 1% Ogawa proportion method have been reported. In the present study, the sensitivity, specificity, and overall efficiency of MGIT AST on the prevalent strains in Japan were all beyond 95%, and considered sufficient as the anti-tuberculosis drug susceptibility testing (AST), though 2.7% of discrepancy was observed. Even for the discrepant cases, there was no difference in the treatment outcome and prognosis. Thus, MGIT AST was confirmed as a reliable AST method comparable to Ogawa standard. However, MGIT AST might increase the proportion of INH resistance if it was used as a major AST method, compared with Ogawa.

[Evaluation of accuracy of clinical diagnosis of TB by annual autopsy report].

PURPOSE: To investigate the accuracy of clinical diagnosis of TB in Japan in recent years and to compare them with previous studies. METHOD: Data (sex, age, clinical diagnosis, pathological diagnosis as cause of death) on deceased cases clinically or pathologically diagnosed ante mortem as having tuberculosis was collected from annual reports of the pathological autopsy cases in 1984, 1989, 1994, and 1999-2004. Information on TB death from population statistics in those 9 years also was collected and compared with data of autopsied cases. RESULT: Autopsy rate in these years was stably around 10 %. Comparison of gender ratio and mean age between the two surveys showed similar numbers. During 1999-2004, 1725 death cases were diagnosed as TB clinically or pathologically. Number of pathologically proven pulmonary TB cases was 429 and that of miliary TB was 283. 55.7% of pulmonary tuberculosis and only 21.9% of miliary tuberculosis were correctly diagnosed before death. Out of 156 cases clinically diagnosed as non-TB diseases but proven as TB pathologically, 30.8% of clinical diagnosis was pneumonia and/or bronchitis, followed by diagnoses of interstitial pneumonia, respiratory failure, pneumoconiosis and lung cancer. However, the main clinical diagnoses of 175 miss-diagnosed miliary TB cases were diseases other than pulmonary diseases such as renal failure, malignant diseases and sepsis. CONCLUSION: In order to reduce undiagnosed pulmonary TB cases and to prevent nosocomial TB infection, differential diagnosis among pneumonia and/or bronchitis cases should be done. In case of miliary TB, not only pneumonia but also diseases other than pulmonary diseases such as renal failure, malignant diseases and sepsis should be included in the list differential diagnosis.

[Treatment results of rifampicin (RFP) resistant isoniazid (INH) susceptible tuberculosis, a hospital based study].

PURPOSE: To evaluate treatment results of Rifampicin (R) resistant Isoniazid (H) susceptible tuberculosis cases. METHOD: Cohort analysis of twenty-three H susceptible R resistant tuberculosis cases started treatment in 1985-2004 at Fukujuji Hospital, by the retrospective review. RESULTS: Three cases became Multi-drug resistant tuberculosis (MDR TB), seventeen cases were cured, two cases died, and one case transferred out. One started treatment with HR became MDR, one of the two started treatment with HR+ Ethambutol (E) became MDR and one of them was cured, eight among ten cases started treatment with HR+Pyrazinamide + (E or Streptomycine (S)) were cured, one among the ten died and one among the ten transferred out, one started treatment with RZE was cured, three among the five cases started treatment with three effective drugs without Z were cured, one among the five died, one among the five became MDR. Three cases started treatment with four effective drugs were cured. Among the nineteen cases continued treatment for more than six months, ten cases treated with four or five effective drugs for at least two months were cured, two cases of nine cases treated with three drugs or less became MDR, seven of the nine cases were cured. Among the same nineteen cases, eleven cases not treated with two or less effective drugs were cured, one case treated with two or less effective drugs for six months became MDR and one of them treated with one or two effective drug for one to three months became MDR and some were cured. The used drugs were H, E, Pyrazinamide, Streptomycin, Kanamycin, Ethionamide and New Quinolones. The duration of treatment of cured cases were eleven to twelve months in 3 cases, twelve to eighteen months in 3 cases, eighteen to twenty-four months in 8 cases and more than two years in 3 cases. CONCLUSION: If the starting regimen is HRZE, we can cure R resistant H susceptible tuberculosis by the use of four effective drugs for more than two months and at least three effective drugs with the total duration of treatment for twelve to twenty-four months.

[A case of multidrug-resistant pulmonary tuberculosis cured by the regimen including thiacetazone].

A 30 years-old-male was referred to our hospital for surgical treatment of multidrug-resistant tuberculosis in April 1998, three years after diagnosis of tuberculosis. All first-line anti-tuberculosis drugs and second-line anti-tuberculosis drugs were resistant on drug susceptibility tests by Ogawa medium. The right upper lobectomy was done because of massive hemoptysis and enlargement of cavitary lesion in June 1998, but this surgical operation was complicated with, bronchial fistula and chronic empyema. Open drainage surgical treatment for chronic empyema was done one month after lobectomy. Sputum culture for M. tuberculosis converted 4 months after the lobectomy, but bacteriological relapse occurred 17 months after initial operation. The new cavitary lesion on middle left lung field developed and sputum smear and culture were continuously positive. Immunotherapy with interferon-gamma via aerosol didn't show any clinical effect. Thiacetazone, sparfloxcin, pyrazinamide, cycloserine was prescribed after 21 months of the initial operation. Four months after changing the regimen sputum smear and culture converted to negative. Chemotherapy was terminated in June 2003, two years after negative conversion. Three years after the termination of treatment no relapse occurred. We considered thiacetazone was effective in this case, because all of the drugs was companied with thiacetazone were resistant by the drug susceptibility tests and were previously used.

[Frequency of MDR-TB/XDR-TB strains isolated from chronic pulmonary tuberculosis patients in Japan].

PURPOSE: To observe the frequency of MDR-TB/XDR-TB strains isolated from chronic pulmonary tuberculosis patients in Japan. OBJECT: Ad hoc National Tuberculosis Survey 2000 on frequency of MDR-TB and XDR-TB strains. MATERIALS AND METHOD: Four hundred and thirty four clinical isolates were collected by the Ad hoc National Tuberculosis Survey 2000, the drug susceptibility testings (proportion method, MGIT Middlebrook, and BrothMIC NTM) were conducted on these strains. These clinical isolates were obtained from patients registered at Health Centers in Japan by the end of 1999 who were culture-positive in 1999 and were registered before January 1st, 1998. The isolates used in this study were selected from patients who were culture-positive at shortest 2 years after the registration. RESULT: The clinical isolates resistant to both INH and RFP were 321 out of 434 (74.0%). The 180 MDR-resistant clinical isolates were also resistant to levofloxacin and amikacin and/or kanamycin. These phenotypes are XDR-TB. No previously registered cases were 165, and previously registered cases were 143 and unknown cases were 13 out of 321 MDR-TB. In 180 XDR-TB cases, no previously registered cases were 95, previously registered cases were 78 and unknown cases were 7. In no previously registered cases, more than 50% cases started treatment in 1990s. Approximately 50% of previously registered patients started treatment in 1960s and 1970s. CONCLUSION: We performed drug susceptibility testing for 434 clinical isolates which were culture-positive at shortest 2 years after registration. No. of MDR-TB patients was 321 and that of XDR-TB patients was 180. The treatment outcome of these patients have to be followed up carefully at Health Centers. The frequency of amikacin resistance was relatively high. This may be due to either common use of amikacin or cross-resistance against streptomycin and kanamycin.

[New cohort analysis system in new tuberculosis surveillance system in Japan].

PURPOSE: To know factors to influence treatment outcome of new cohort analysis method in revised TB surveillance system and important points for quality improvement of the system using hospital based real data of TB patients. METHODS: To analyze treatment outcome of new sputum smear positive TB patients hospitalized to Fukujuji Hospital during 2004 year by new cohort analysis method. RESULTS: One hundred and ninety-four TB patients were hospitalized. Out of them, 166 were new cases. Cohort analysis showed 104 treatment success cases (62.7%), 27 died cases (16.3%), 2 failure cases (1.2%), 9 defaulter cases (5.4 %), 15 transfer-out cases (9.0%), 7 cases with treatment longer than 1 year (4.2%), and 2 other cases (1.2%). Among 27 died cases, 18 cases were due to TB death. Out of other 9 cases, 4 were due to malignancy, 3 due to pneumonia, and 2 other causes. Out of 9 defaulter cases, 6 were self-interruption, 2 were due to medical doctor's decision to resolve side effects. Out of 7 cases with treatment longer than 1 year, half were due to drug resistance and another half were due to side effects. Twenty-eight retreatment cases showed 15 treatment success, 4 failure cases, 5 transferred-out, 2 cases with longer treatment than 1 year, and 2 other cases. DISCUSSION: To evaluate TB treatment outcome, died cases should be categorized into TB death and non-TB death. Defaulter cases and cases with treatment longer than 1 year should be categorized by causes into drug resistant cases and cases with interruption by side effects. At national level, data collection of drug sensitivity test results and development of cohort analysis method for drug resistant cases, especially multi-drug resistant cases, are needed to make new cohort analysis method more relevant to TB treatment outcome.

[Microbiologically identified isolates of Mycobacterium heckeshornense in two patients].

PURPOSE: To identify mycobacteria isolated from sputa of a 51-year-old female and a 72-year-old male patient with pneumoconiosis. OBJECT AND METHOD: Mycobacteria species were isolated from sputa of a 51-year-old female. The culture was always negative in spite of positive smears before the final isolation in 1988. A 72-year-old male patient suffered from pneumoconiosis and the acid-fast bacillus was isolated by routine sputum examination in 2003. These two strains of acid-fast bacilli were identified as Mycobacterium heckeshornense by partial sequencing of 16S rRNA and rpoB and conventional methods (biochemical and routine culture methods). RESULT: These two strains grew on 1% Ogawa's slant medium at 37 degrees C and 42 degrees C, but not at 28 degrees C. They formed yellowish colonies in the dark (Scotochromogen). They were classified as a slowly growing Mycobacteria. As it was difficult to distinguish M. heckeshornense from M. xenopi by conventional methods including growth rate, temperature range of mycobacterial growth, light coloration reaction, biochemical and biological tests, virulence using guinea pigs and drug susceptibility test were further explored. Finally two were identified as M. heckeshornense by summing of these results. CONCLUSION: Mycobacteria species that grow at 42 degrees C for four weeks, imply M. xenopi with a DDH method. It is essential to perform both sequencing of 16S rRNA and rpoB gene and a biochemical method for the purpose of distinguishing M. heckeshornense from M. xenopi.